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Neeraj Agarwal: Welcome to UroToday. Today we have Dr. Duncan Gilbert from the MRC Clinical Trials Unit at University College London. Today we will be asking him to talk about his data he recently presented with his team comparing transdermal estradiol with luteinizing hormone-releasing hormone agonists in patients with non-metastatic prostate cancer, and how these two drugs compare as far as androgen suppression is concerned. So welcome, Duncan, and thanks for taking the time.

Duncan Gilbert: Thank you, Neeraj. I'm just going to show you through the presentation that my colleague, Professor Ruth Langley, chief investigator on the PATCH trial, presented at ESMO. What I'm presenting are the primary oncological results from a Phase III randomized controlled trial investigating transdermal estradiol versus LHRH analogues for androgen suppression in locally advanced prostate cancer. At this point, I want to say that PATCH as a trial and as a concept was the brainchild of Professor Paul Abel, who led the trial for many years and is sadly no longer with us, but PATCH and all the results from this are very much dedicated to him and his hard work. PATCH was funded by Cancer Research UK and run from the MRC Clinical Trials Unit at UCL, as was the sister trial STAMPEDE.

To investigate transdermal estradiol as a mechanism for androgen suppression in prostate cancer, we've performed an adaptive Phase II/III trial program. And the essence of this is that transdermal estradiol is an alternative to LHRH analogues in that it causes androgen suppression through a negative feedback effect, but without the estrogen depletion effects that are seen through LHRH analogues or through conventional androgen suppression. The point about that, or the potential advantage for that, is that it avoids those side effects that are attributable to a low estrogenic state in men which are not required for the treatment of prostate cancer but are seen as a result of androgen suppression.

Now, estradiol and stilbestrol were used for many years as a treatment for prostate cancer but have some particular side effects around cardiovascular toxicity attributable to the first-pass effect through the liver. So in particular, increased risk of deep vein thrombosis, PEs, and ischemic heart disease. A transdermal approach—so using patches—avoids this, and the adaptive components of the trial have sequentially tested estrogen patches, both to begin with for cardiovascular, then a pre-planned interim efficacy analysis, and now the results that we presented at ESMO are for the final Phase III oncological outcomes in the M0 patients. So that's the locally advanced non-metastatic patients. This ultimately was a randomized trial, Phase III level, of 1,360 men with locally advanced prostate cancer.

This was de novo men about to start androgen deprivation. They were randomized in the experimental arm to transdermal estradiol, which are patches that release 100 micrograms of estradiol every 24 hours, initially to four patches changed twice weekly, and then once the testosterone was suppressed, titrated down to three patches changed twice weekly. The primary outcome of the data that we're going to show in this cohort was metastasis-free survival. And this was a non-inferiority study, with a plan to rule out an absolute 4% detriment in three years' metastasis-free survival with 85% power and one-sided significance of 5%.

1,360 patients were randomized across the UK. Baseline characteristics were well-balanced. Median age of the patients was 72 years, and the median PSA 24. The majority of the patients had T3 disease and 65% were N0. The key slide and key results: the primary outcome measure of metastasis-free survival was that transdermal estradiol met its non-inferiority target with a hazard ratio of 0.96, slightly in favor of transdermal estradiol. So non-inferiority was demonstrated, and in fact excluded a 2% difference in metastasis-free survival. Similarly, the outcomes were non-inferior for overall survival as a secondary outcome.

Importantly, across these patients, there were similar rates of castration. The main difference in terms of toxicity—and we might want to talk about that a little more in a moment—was that in the patients receiving transdermal estradiol, hot flushes were significantly reduced as compared with patients on LHRH analogues. Conversely, patients with transdermal estradiol reported higher rates of gynecomastia.

Now, previously, along the way as we've developed this, we've shown that in a sub-study that patients treated with transdermal estradiol actually improved their bone mineral density. Obviously, bone health is a significant toxicity facing our patients with prostate cancer on long-term androgen deprivation, and so in a previously published sub-study, patients treated with tE2 as their androgen deprivation gained bone health as compared with LHRH analogues. We've also shown in a pre-planned cardiovascular analysis that there's no excess cardiovascular toxicity. This was published in The Lancet a couple of years ago, showing no difference in cardiovascular toxicity between patients commenced on tE2 versus LHRH analogues. We've also published data to show an improved overall quality of life in patients receiving tE2 as compared with LHRH analogues.

The conclusion from the data presented at ESMO by Professor Langley was that tE2 was as effective as an LHRH analogue, with no detriment in terms of prostate cancer outcomes or overall survival in starting androgen deprivation for locally advanced prostate cancer, and that transdermal estradiol therefore provides a choice about expected side effects and route of administration, allowing for personalized treatment plans in patients. And we believe that transdermal estradiol should be considered a standard-of-care androgen deprivation option in men with non-metastatic prostate cancer.

Neeraj Agarwal: Thank you very much, Duncan. This was great. Very pertinent trial. Congratulations to you and the group at the MRC Clinical Trials Unit for conducting such a pertinent study. I'll ask you some of the questions which have come up right after the fantastic presentation by Dr. Langley at the ESMO meeting. First question is, how does it impact our patients who are experiencing severe hot flushes and they really want to change their LHRH agonists to something else? What is your advice for them?

Duncan Gilbert: I think really importantly, and an important first step, is that this is a repurposing program, so at present, transdermal estradiol isn't licensed for use for men with prostate cancer. And that is a process that we are now going through in the UK with the MHRA to try and extend the license for transdermal estradiol. So there is that immediate here-and-now challenge to usage.

But with respect to your question in terms of how it offers men choice, what the trial has shown sequentially—and we can now say—is that estrogen patches are as good in terms of the actual treatment for prostate cancer for men. And in a way, we shouldn't be surprised by that. We've shown along the way that there is good at causing castrate levels of testosterone, we've shown they're cardiovascularly safe. But I think, as you rightly said, a key difference is that because we avoid these estrogenic side effects of testosterone suppression with LHRH, then the men have a significantly reduced rate of hot flushes.

In the PATCH trial, in the tE2 comparison in STAMPEDE as presented at ESMO, those rates were about 80% of men reported any hot flushes on LHRH analogues, and that was halved in the men receiving transdermal, and it was conversed with gynecomastia. Now, we have more nuanced patient-reported outcomes from our quality of life paper that we published in BJUI International several years ago. And there, patients reported kind of bothersome hot flushes—so hot flushes that really troubled them—around 40% of the time. That was reduced to 5% in patients on estrogen patches. And again, the figures are remarkably similar. Around 40% of men reported any bothersome breast tenderness or swelling—gynecomastia—down as compared with about 5-7% on LHRH analogues.

So I think that's kind of why we're proposing this as a choice for men. Absolutely, there'll be some men for whom an increased risk of gynecomastia is a real problem and a real deal-breaker, and therefore it's not for them. But similarly, I think as someone who treats lots of men with prostate cancer will know, hot flushes, the sleeplessness associated with that, the fatigue associated with that are significant. And I think, for that reason, I envisage that there will be a significant proportion of men who will be keen to try estrogen patches for the treatment of prostate cancer when they're then available.

Neeraj Agarwal: I agree with you, this can be a game-changer for many men who have intolerable hot flushes, and this has been a major issue in our clinics in many of our patients. Regarding gynecomastia, if you come across gynecomastia, what has been your approach to treating that issue on transdermal estradiol?

Duncan Gilbert: Yeah. We have some limited data on men who received—well, prophylactic is obviously better—breast bud irradiation as a treatment. Now, obviously we've got a huge wealth of data from the trial that we haven't yet presented and that we're working through now that we've got the top-level oncological results. And that's definitely a key question, is whether prophylactic breast bud irradiation prevents the gynecomastia seen on tE2. I think, from clinical experience, it's more likely to work prophylactically than once gynecomastia is established. And obviously there will be some men for whom the radiotherapy is not desirable, and so we need to understand that. Also, we need to understand second malignancy rates across the board as well. And we will have that data in due course.

Neeraj Agarwal: Thank you. First of all, this transdermal estradiol seems to improve hot flushes, improve bone density without compromising cardiovascular safety, and have equal oncologic outcomes. That is the crux as far as the results are concerned. So moving forward, if you talk about metastatic prostate cancer—and of course we don't have those data right now—how do you foresee combining transdermal estradiol with androgen receptor pathway inhibitors? Because I think that will be the question of immediate interest for many of our patients who have metastatic disease and they have these debilitating hot flushes. I'm sure this question is going to come up for all of us.

Duncan Gilbert: Absolutely. And both hot flushes and bone health in men with metastatic disease. So we've presented here the results from the locally advanced non-metastatic cohort, but as you saw from the slide some years ago, as alongside STAMPEDE and many other trials, we divided our trial and our cohorts into individually powered locally advanced and then metastatic patients. So we have a metastatic cohort of men who, again, were randomized between LHRH analogues and transdermal estradiol. And within that cohort, over the latter proportion of those patients who were randomized was after the data showing novel androgen receptor signaling inhibitors were now a standard of care. And in a pre-planned, we've collected prospective data from patients who were randomized to transdermal estradiol and then received one of those novel androgen receptor signaling inhibitors—so particularly either abiraterone or then enzalutamide reflecting UK practice at the time.

So we have that prospective data, both looking around any additional toxicity signals, but also efficacy in terms of both androgen suppression, PSA responses, and those data are going to be presented at a forthcoming conference next year. We're hopeful that the final primary outcome data, in terms of that metastatic cohort, will also be ready within the next 12 to 18 months.

Neeraj Agarwal: Thank you very much for the wonderful presentation and for taking the time, Duncan. To conclude this discussion, any final message for our audience before we conclude our meeting today?

Duncan Gilbert: Only really to say thank you to the funders, to Cancer Research UK and the MRC, but also all the patients, their families who have agreed to be enrolled in a trial and given us their data over these years. It's been a 15-year project, and it's fantastic at this point to see the primary data. So really just a big thank you on behalf of a huge trial team and Professor Langley, chief investigator, who I'm representing today.

Neeraj Agarwal: And thank you for joining us, Duncan. Congratulations again.

Duncan Gilbert: Thank you.